The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4, and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various disease states are also discussed in the book by Rokach.
Recently a number of compounds of formula (1) in which A represents optionally substituted heterocycle, and pharmaceutically acceptable salts thereof, have been disclosed as leukotriene antagonists and inhibitors of leukotriene biosynthesis. ##STR1##
EP 480,717 discloses compounds of formula (1) in which A represents optionally substituted quinoline; more specifically disclosed is the compound in which A represents 7-chloro-2-quinolinyl. U.S. Pat. No. 5,270,324 discloses two compounds of formula (1) in which A represents 6-fluoro- or 6,7-difluoro-2-quinolinyl. In EP 604,114 there is disclosed compounds in which A is halo-substituted thieno[2,3-b]pyridine, particularly 2,3-dichlorothieno[2,3-b]pyridin-5-yl. Compounds of formula (1) are useful in the treatment of asthma as well as other conditions mediated by leukotrienes, such as inflammation and allergies.
In the afore-mentioned references, the thiomethylcyclopropaneacetic acid moiety of compounds of formula (1) is introduced using methyl 1-(thiomethyl)cyclopropaneacetate. While in EP 480,717 methyl 1-(thiomethyl)cyclopropaneacetate is prepared from 1,1-cyclopropanedimethanol by stepwise transformation of the two hydroxy groups into the thiol and carboxylate moieties, an improved synthesis is used in U.S. Pat. No. 5,270,324 and EP 604,114, which involves first converting 1,1-cyclopropanedimethanol into the corresponding cyclic sulfite using thionyl chloride.
Subsequently, it has been discovered that 1-(thiomethyl)cyclopropaneacetic acid can be prepared from 1-(acetylthiomethyl)cyclopropaneacetonitrile by conducting the hydrolysis in a biphasic system, the product may then be crystallized from a hydrocarbon such as hexane or heptane. The dilithium salt of 1-(thiomethyl)cyclopropaneacetic acid, generated in situ, is used in the preparation of compounds of formula (1).
In the previous process for preparing 1-(thiomethyl)cyclopropaneacetic acid, the method for preparing cyclic sulfite results in a number of by-products thereby reducing the yield of the desired cyclic sulfite; the process also requires multiple aqueous extractions, and solvent switches rendering it difficult to adapt to large scale production. Accordingly, there exists the need for an efficient synthesis of 1-(thiomethyl)cyclopropaneacetic acid which is amenable to scale-up, and provides improved overall product yield.